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Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome.

Publication ,  Journal Article
Xu, K; Wang, K; Yang, Y; Yan, D-A; Huang, L; Chen, C-H; Xiao, Z
Published in: Eur J Med Chem
June 15, 2015

A series of linear peptides (6a-6o) were designed based on the known non-covalent 20S proteasome inhibitors TMC-95A and compound 5 via a fragment-based approach. These compounds were synthesized and evaluated against the chymotrypsin-like activity of the human 20S proteasome. Three of them (6d, 6e and 6k) were potent inhibitors with IC50 values at the submicromolar level. These three compounds were selective to the β5-subunit and showed no obvious inhibition against trypsin-like and caspase-like activities of the human 20S proteasome. Docking study of the most potent compound 6e revealed its key interactions with the β5-subunit of the 20S proteasome. These findings have provided a new chemical template for non-covalent proteasome inhibitors, which is ready for further structural optimization to improve both potency and subunit selectivity.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

June 15, 2015

Volume

98

Start / End Page

61 / 68

Location

France

Related Subject Headings

  • Proteasome Endopeptidase Complex
  • Protease Inhibitors
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Drug Discovery
  • Binding Sites
  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Xu, K., Wang, K., Yang, Y., Yan, D.-A., Huang, L., Chen, C.-H., & Xiao, Z. (2015). Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome. Eur J Med Chem, 98, 61–68. https://doi.org/10.1016/j.ejmech.2015.05.023
Xu, Kai, Ke Wang, Ying Yang, Ding-An Yan, Li Huang, Chin-Ho Chen, and Zhiyan Xiao. “Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome.Eur J Med Chem 98 (June 15, 2015): 61–68. https://doi.org/10.1016/j.ejmech.2015.05.023.
Xu K, Wang K, Yang Y, Yan D-A, Huang L, Chen C-H, et al. Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome. Eur J Med Chem. 2015 Jun 15;98:61–8.
Xu, Kai, et al. “Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome.Eur J Med Chem, vol. 98, June 2015, pp. 61–68. Pubmed, doi:10.1016/j.ejmech.2015.05.023.
Xu K, Wang K, Yang Y, Yan D-A, Huang L, Chen C-H, Xiao Z. Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome. Eur J Med Chem. 2015 Jun 15;98:61–68.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

June 15, 2015

Volume

98

Start / End Page

61 / 68

Location

France

Related Subject Headings

  • Proteasome Endopeptidase Complex
  • Protease Inhibitors
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Drug Discovery
  • Binding Sites
  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 3214 Pharmacology and pharmaceutical sciences
  • 1115 Pharmacology and Pharmaceutical Sciences